Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.
Todorovic. Aleksandar A; Ericson. Mark D MD; Palusak. Ryan D RD; Sorensen. Nicholas B NB; Wood. Michael S MS; Xiang. Zhimin Z; Haskell-Luevano. Carrie C
Key Findings
- Replacing Glu at position 5 with alanine cuts potency 15‑ to 37‑fold depending on the receptor for α‑MSH, but the same change doesn’t have the same impact on NDP‑MSH.
- Alanine changes at other sites also altered activity, showing that residues outside the classic His‑Phe‑Arg‑Trp core matter for receptor binding.
- The structure‑activity relationship of α‑MSH does not reliably predict that of the synthetic NDP‑MSH, indicating different interaction patterns with melanocortin receptors.
Practical Outcomes
- For DIY users of melanotan‑I (an α‑MSH analog), the data suggest that tweaking the peptide sequence can lead to unpredictable changes in effectiveness. It warns against assuming that modifications that improve one version will help another, so any experimental changes should be approached with caution and thorough testing.
Summary
The study swapped individual building blocks (alanine) into two related skin‑pigment peptides—natural α‑MSH and the synthetic, stronger NDP‑MSH—to see how each change affects activity at mouse receptors. It found that some swaps dramatically reduced activity, but the effects weren’t the same for the two peptides, meaning you can’t assume what works for one will work for the other.
Abstract
The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.
Study Information
pubmed
2016
2016-05-17T00:00:00.000Z
10.1021/acschemneuro.6b00098
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